Small RNAs, big impact: microRNAs in malaria pathogenesis, therapeutic opportunities, and challenges

Malaria is one of the world's most critical parasitic diseases; it is caused by Plasmodium species and spreads through Anopheles mosquitoes. The life cycle of Plasmodium species is complex and involves several stages in humans and mosquitoes, each involving distinct molecular interactions. Recent molecular biology research has suggested that host microRNAs (miRNAs) may serve as important regulators of host-parasite interactions during malaria infection. MicroRNAs, approximately 22 nucleotides long, are non-coding RNAs that control gene expression by binding to target mRNAs and either repressing translation or causing mRNA degradation. During infection, host miRNAs are actively regulated and can directly target parasite transcripts or influence host cellular pathways essential for parasite survival and disease development. The role of human miRNAs has not yet been fully explored in malaria. This report aims to integrate evidence from the literature, molecular mechanisms, and translational insights to summarize the current knowledge in miRNA research and to guide the diagnosis and treatment of malaria using miRNAs. Here, we focus on the mechanistic and cell-type-resolved dimension of host miRNA action in malaria: the extracellular vesicle-mediated transfer of AGO2-miRNA complexes between infected erythrocytes and recipient endothelial cells, the bidirectional host-parasite miRNA traffic that allows human miRNAs to repress parasite transcripts, and the tissue-specific miRNA programs that shape organ-specific pathology. We also delineate the principal knowledge gaps related to causality versus correlation, cell-of-origin attribution, and translational barriers to miRNA therapeutics that must be resolved before miRNAs can be deployed diagnostically or therapeutically in malaria.